Acute and chronic pain are common in children and adolescents and are often associated with severe functional disability and mood disorders. The pharmacological treatment of chronic pain in children and adolescents can be challenging, ineffective, and is mostly based on expert opinions and consensus. We are examining new strategies to effectively treat pain in children, which are based on mechanistic approaches and that are non-opioid based. One such approach is the use ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, which has been used as an adjuvant to opioids in adult chronic pain and has been shown, in some instances, to decrease pain and minimize opioid-requirement. The use of sub anesthetic ketamine as an analgesic is supported by evidence, both from animal and human studies, implicating activation of NMDA receptors in the pathobiology of nociceptive, inflammatory, and neuropathic pain and in central sensitization. In addition, activation of NMDA receptors has also been show in animals and in human experimental studies to play a role in settings where acute or chronic use of opioids is associated with tolerance or opioid-induced hyperalgesia. Therefore, based on these preclinical findings, ketamine has been examined clinically as an adjuvant to opioids for the treatment of acute and chronic pain and in settings of opioid-induced hyperalgesia. We examined the effects of sub-anesthetic ketamine on pain intensity and opioid use in children and adolescents with acute and chronic pain syndromes treated both in inpatient and outpatient settings. We have shown that sub anesthetic doses of ketamine can be safely administered to children and adolescents both on an inpatient and outpatient settings, and in low doses it has an acceptable side-effect profile. Overall, in children with chronic pain, ketamine significantly reduces pain intensity, especially in the setting of complex regional pain syndrome. However, in patients admitted to the hospital, the effect of ketamine on pain scores varied according to clinical diagnosis, infusion duration, and pain location and greater reductions in pain scores are observed in patients with cancer pain. Another approach we are also evaluating for the management of acute pain during the perioperative setting is the use of dexmedetomidine, an alpha2-adrenoreceptor agonist with sedative and analgesic properties. A number of animal studies support the hypothesis that dexmedetomidine may have a role in the treatment of pain. For example, in neuropathic pain models, the antinociceptive effect of dexmedetomidine appears to be opioid independent and is associated with supraspinal facilitation of inhibitory postsynaptic currents as well as inhibition of sensory neurons from the substance gelatinosa. In models of visceral pain, dexmedetomidine has antinociceptive effects unrelated to opioid receptor activation and are associated with increased nitric oxide availability. We have previously shown that in children undergoing tonsillectomies, dexmedetomidine improves pain management and prolongs opioid-free intervals during the immediate post-operative period. Additionally, in obese adolescents undergoing bariatric surgery, the intraoperative administration of dexmedetomidine decreases opioid utilization during the perioperative period. Another setting associated with acute and chronic pain in children is that of sickle cell disease. In the laboratory, we had previously shown that dexmedetomidine ameliorates the altered nociception phenotype in mouse models of sickle cell disease. We are now examining the role for dexmedetomidine in pain management during vaso-occlusive episodes in sickle cell patients. We have preliminary findings suggesting possible beneficial effects of dexmedetomidine in decreasing opioid requirements and supporting the hypothesis that dexmedetomidine may have a role as a possible analgesic adjuvant to mitigate vaso-occlusive-episodes-associated pain in patients with sickle cell disease. Overall we have collected data on the feasibility and safety of new approaches to treat pain in children, such as the administration of sub anesthetic ketamine or the use of an alpha2 agonist, such as dexmedetomidine. These data will inform the design, sample and effect sizes calculations for the conduct of larger randomized clinical trials to identify pediatric patients who could benefit from those strategies